Stressors

Level of Biological Organization

Organ term

Taxonomic Applicability

Life Stages

Sex Applicability

How This Key Event Works

The occurrence of altered hepatic foci (AHF) as precursors to liver tumors in AFB1-treated rats has been recognized for decades. Originally, these foci were observed as histologically different from the surrounding parenchyma. [1-4] In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). [5-8] The growth and occurrence of foci are expressed as the number of AHF in a volume of liver, possibly the entire liver, and the volume fraction of the liver occupied by AHF. [9] Both of these reflect focal growth because single cell foci are not detectable with the immunohistochemical staining technique. The assumption is that single transformed cells in which apoptosis is blocked by tumor-critical mutations will grow into AHF. [10] A number of agents regarded as tumor promoters appear to enhance the growth of foci, acting to further inhibit apoptosis and also creating an overall proliferative stimulus. [11,12]
AFB1 appears to be a “complete” carcinogen in that the toxin acts as an initiator through the formation of pro-mutagenic DNA adducts (the MIE) and as a promoter through increasing oxidative stress and inflammation. [13,14]

How It Is Measured or Detected

Quantitative stereology has been used to quantify the growth of AHF. [6,15-17] Growth of foci appears to follow the Moolgavkar-Venzon-Knudson model of initiation and promotion. [18,19] Most recently, Johnson et al. (2014) have shown that a chemoprotective agent reduces the occurrence of AHF to background levels and completely protects against tumors [20], although pro-mutagenic adducts are still present at easily quantifiable levels.

16. Xu YH, Maronpot R, Pitot HC (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.

17. Xu YH, Campbell HA, Sattler GL, Hendrich S, Maronpot R, et al (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res 50: 472-479.